Persistent neuronal Ube3a expression in the suprachiasmatic nucleus of Angelman syndrome model mice

Abstract

Mutations or deletions of the maternal allele of the UBE3A gene cause Angelman syndrome (AS), a severe neurodevelopmental disorder. The paternal UBE3A/Ube3a allele becomes epigenetically silenced in most neurons during postnatal development in humans and mice; hence, loss of the maternal allele largely eliminates neuronal expression of UBE3A protein. However, recent studies suggest that paternal Ube3a may escape silencing in certain neuron populations, allowing for persistent expression of paternal UBE3A protein. Here we extend evidence in AS model mice (Ube3am–/p+) of paternal UBE3A expression within the suprachiasmatic nucleus (SCN), the master circadian pacemaker. Paternal UBE3A-positive cells in the SCN show partial colocalization with the neuropeptide arginine vasopressin (AVP) and clock proteins (PER2 and BMAL1), supporting that paternal UBE3A expression in the SCN is often of neuronal origin. Paternal UBE3A also partially colocalizes with a marker of neural progenitors, SOX2, implying that relaxed or incomplete imprinting of paternal Ube3a reflects an overall immature molecular phenotype. Our findings highlight the complexity of Ube3a imprinting in the brain and illuminate a subpopulation of SCN neurons as a focal point for future studies aimed at understanding the mechanisms of Ube3a imprinting.

Human cerebral organoids capture the spatiotemporal complexity and disease dynamics of UBE3A

“…In neurons of 1-7 week old hCOs, UBE3A was nuclear, but upon extended culture (10-17 weeks) UBE3A intensity weakened, becoming absent in TUJ1+, MAP2+, TBR1+ and SATB2+ neurons ( Figure 3C, 3E, 3F, S3A, and S3C-E). Interestingly, immature SOX2+/TUJ1+ neurons did exhibit nuclear UBE3A in 10-12-week old AS hCOs, consistent with previous reports of paternal UBE3A expression in immature neurons (Grier et al, 2015;Jones et al, 2016;Judson et al, 2014;Sato and Stryker, 2010) (Figure S3F). Collectively, these results suggest hCOs exhibit successful imprinting and that this process may be occurring very early in human fetal development.…”

Prader-Willi locus Snord116 RNA processing requires an active endogenous allele and neuron-specific splicing by Rbfox3/NeuN

“…Ube3a, another gene within the 15q11-q13 locus, is paternally imprinted in neurons, in which the paternal expression of the Snrpn-Ube3a transcript extends through the anti-sense to Ube3a, blocking transcription of paternal Ube3a and leading to maternal-specific expression (39)(40)(41). Interestingly, in Rbfox3/NeuN-negative cells of the suprachiasmatic nucleus (SCN), paternal Ube3a expression is observed (42). Due to its high level of GC-skew, transcription through Snord116 results in the formation of R-loops, modulating the balance between chromatin state and transcription elongation.…”

Angelman syndrome and melatonin: What can they teach us about sleep regulation

“…36 This relaxation in the imprinting of the paternal Ube3a allele is specific to the SCN, as UBE3A is absent from nearly all other brain regions in these mice. [36][37][38] Altogether, although UBE3A may regulate BMAL1 stability and cellular clock function, it is not clear that its loss in AS simply results in changes in Process C that explain the severe sleep disorders described for these patients.…”